title: XPD DNA nucleotide excision repair gene polymorphisms associated with DNA repair deficiency predict better treatment outcomes in secondary acute myeloid leukemia.
abstract: Pharmacogenetic studies in DNA repair pathway have consistently demonstrated correlations between the XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes, previously associated with suboptimal DNA repair, and differential cancer treatment outcomes. We evaluated these polymorphisms and XPD haplotypes in adult de novo (n=214) and secondary (n=79) acute myeloid leukemia (AML) patients treated with cytarabine and anthracycline chemotherapy. Genotyping was performed by MALDI-TOF mass spectrometry. Logistic and proportional hazards regression models were used to evaluate relationships. Differential responses were observed in secondary, but not de novo, AML. Among secondary AML patients, the odds of achieving complete remission (CR) were higher for the XPD 312Asn/Asn (OR= 11.23; 95% CI, 2.23-56.63) and XPD 751Gln/Gln (OR= 7.07; 95% CI, 1.42-35.18) genotypes. The XPD diplotypes were coded as the combination of two of the following haplotypes: haplotype A=(Lys)751A/(Asp) 312G; B=(Gln)751C/(Asn)312A; C=(Lys)751A/(Asn)312A; and D=(Gln)751C/(Asp)312G. The BB diplotype was associated with CR attainment [OR=18.31; 95% CI: 2.08-283.57] and longer survival [HR=0.31; 95% CI: 0.14-0.73] compared to the referent AA diplotype. The XPD 751 CC, 312GA, 312AA genotypes and the XPD DC diplotype were also associated with longer overall survival (OS).Thus, XPD codon 312 and 751 variant genotypes and haplotypes containing at least one variant allele may predict better treatment responses. If validated, these findings could support stratification of chemotherapy in secondary AML.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kuptsova-Clarkson
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Joli
authors.initials: J
authors.lastname: Weiss
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Lara E
authors.initials: LE
authors.lastname: Sucheston
authors.forename: Gary
authors.initials: G
authors.lastname: Zirpoli
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kopecky
authors.forename: Laurie
authors.initials: L
authors.lastname: Ford
authors.forename: Javier
authors.initials: J
authors.lastname: Blanco
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich